Costimulation blockade represents a new class of immunosuppression with more specific targets accompanied by less toxicity. Belatacept is the first FDA approved costimulation blockade reagent for use in kidney transplant recipients. Despite superior renal function, improved cardiovascular risk profile, and significantly better patient and graft survival at 7 years, the high rates of rejection as well as other logistical challenges have limited the breadth of its clinical adoption. We now have the world's largest experience using belatacept in kidney transplant recipients, approaching 1000 patients. We have observed similar benefits in renal function, but were surprised by the high rates of rejection we observed when using it outside the context of a clinical trial, nearly double what was previously reported. It is interesting to note that approximately half of the patients experienced rejection while the other half did not, provoking the question as to why some patients are susceptible while others are resistant to costimulation blockade therapy. Our early studies in mice and non- human primates (NHP) identified costimulation blockade resistant rejection as an important area for investigation and emphasized the potential benefits of developing a successful tolerance strategy. One of the most effective methods to promote tolerance in experimental models has been the transient disruption of the CD28 and CD40 pathways during the introduction of donor antigens. We have evaluated the next generation of costimulation blockade reagents (domain antibodies targeting CD28 and CD154) and shown that they are both safe and efficacious. Despite these advances there is still a subset of animals and patients who reject while on therapy. In comparing these rejecting vs. stable recipients, we have identified a memory T cell biomarker that correlated with increased risk of costimulation blockade-resistant rejection in both NHP and humans. We posit that the use of this predictive biomarker may allow us to identify optimal candidates for costimulation-blockade- based tolerance induction therapies, and propose to longitudinally assess the stability and plasticity of this biomarker and test its predictive power in a prospective fashion in animals receiving dual costimulation blockade therapy. Further exploration of critical pathways utilized by costimulation-independent memory T cells and development of next-generation cellular therapies including mesenchymal stromal cells (MSCs) will provide powerful strategies to mitigate the risk of rejection and promote tolerance induction in particularly rejection-prone recipients. The development of tolerance induction protocols based on the immune status of individual recipients will facilitate personalized strategies for transplantation tolerance, to minimize peri- transplant immunosuppression and preserve protective immunity.